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bioRxiv · 10.1101/2022.05.11.491514

Glucose-regulated O-GlcNAcylation of DNMT1 inhibits DNA methyltransferase activity and maintenance of genomic methylation

Shin, H.·Leung, A.·Costello, K. R.·Senapati, P.·Kato, H.·Schones, D. E.
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Abstract

The DNA methyltransferase activity of DNMT1 is vital for genomic maintenance of DNA methylation. We report here that DNMT1 function is regulated by O-GlcNAcylation, a protein modification that is sensitive to glucose levels, and that elevated O-GlcNAcylation of DNMT1 from high glucose environment leads to alterations to the epigenome. Using mass spectrometry and complementary alanine mutation experiments, we identified S878 as the major residue that is O-GlcNAcylated on DNMT1. Functional studies further revealed that O-GlcNAcylation of DNMT1-S878 results in an inhibition of methyltransferase activity, resulting in a general loss of DNA methylation that is preferentially at partially methylated domains (PMDs). This loss of methylation corresponds with an increase in DNA damage and apoptosis. These results establish O-GlcNAcylation of DNMT1 as a mechanism through which the epigenome is regulated by glucose metabolism and implicates a role for glycosylation of DNMT1 in metabolic diseases characterized by hyperglycemia.

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Shin, H., Leung, A., Costello, K. R., Senapati, P., Kato, H., Schones, D. E.. 2022-05-11. Glucose-regulated O-GlcNAcylation of DNMT1 inhibits DNA methyltransferase activity and maintenance of genomic methylation. https://doi.org/10.1101/2022.05.11.491514

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